PMID- 23742180
OWN - NLM
STAT- MEDLINE
DCOM- 20131227
LR  - 20211021
IS  - 1535-4989 (Electronic)
IS  - 1044-1549 (Print)
IS  - 1044-1549 (Linking)
VI  - 49
IP  - 5
DP  - 2013 Nov
TI  - Tissue inhibitor of metalloproteinases-3 moderates the proinflammatory status of 
      macrophages.
PG  - 768-77
LID - 10.1165/rcmb.2012-0377OC [doi]
AB  - Tissue inhibitor of metalloproteinases-3 (TIMP-3) has emerged as a key mediator 
      of inflammation. Recently, we reported that the resolution of inflammation is 
      impaired in Timp3(-/-) mice after bleomycin-induced lung injury. Here, we 
      demonstrate that after LPS instillation (another model of acute lung injury), 
      Timp3(-/-) mice demonstrate enhanced and persistent neutrophilia, increased 
      numbers of infiltrated macrophages, and delayed weight gain, compared with 
      wild-type (WT) mice. Because macrophages possess broad immune functions and can 
      differentiate into cells that either stimulate inflammation (M1 macrophages) or 
      are immunosuppressive (M2 macrophages), we examined whether TIMP-3 influences 
      macrophage polarization. Comparisons of the global gene expression of 
      unstimulated or LPS-stimulated bone marrow-derived macrophages (BMDMs) from WT 
      and Timp3(-/-) mice revealed that Timp3(-/-) BMDMs exhibited an increased 
      expression of genes associated with proinflammatory (M1) macrophages, including 
      Il6, Il12, Nos2, and Ccl2. Microarray analyses also revealed a baseline 
      difference in gene expression between WT and Timp3(-/-) BMDMs, suggesting altered 
      macrophage differentiation. Furthermore, the treatment of Timp3(-/-) BMDMs with 
      recombinant TIMP-3 rescued this altered gene expression. We also examined 
      macrophage function, and found that Timp3(-/-) M1 cells exhibit significantly 
      more neutrophil chemotactic activity and significantly less soluble Fas 
      ligand-induced caspase-3/7 activity, a marker of apoptosis, compared with WT M1 
      cells. Macrophage differentiation into immunosuppressive M2 cells is mediated by 
      exposure to IL-4/IL-13, and we found that Timp3(-/-) M2 macrophages demonstrated 
      a lower expression of genes associated with an anti-inflammatory phenotype, 
      compared with WT M2 cells. Collectively, these findings indicate that TIMP-3 
      functions to moderate the differentiation of macrophages into proinflammatory 
      (M1) cells.
FAU - Gill, Sean E
AU  - Gill SE
AD  - 1 Center for Lung Biology, University of Washington, Seattle, Washington.
FAU - Gharib, Sina A
AU  - Gharib SA
FAU - Bench, Eli M
AU  - Bench EM
FAU - Sussman, Samuel W
AU  - Sussman SW
FAU - Wang, Roy T
AU  - Wang RT
FAU - Rims, Cliff
AU  - Rims C
FAU - Birkland, Timothy P
AU  - Birkland TP
FAU - Wang, Ying
AU  - Wang Y
FAU - Manicone, Anne M
AU  - Manicone AM
FAU - McGuire, John K
AU  - McGuire JK
FAU - Parks, William C
AU  - Parks WC
LA  - eng
GR  - HL098067/HL/NHLBI NIH HHS/United States
GR  - R01 HL089455/HL/NHLBI NIH HHS/United States
GR  - R01 HL082658/HL/NHLBI NIH HHS/United States
GR  - HL082658/HL/NHLBI NIH HHS/United States
GR  - HL093022/HL/NHLBI NIH HHS/United States
GR  - HL089455/HL/NHLBI NIH HHS/United States
GR  - P30 DK017047/DK/NIDDK NIH HHS/United States
GR  - P01 HL098067/HL/NHLBI NIH HHS/United States
GR  - P30 DK089507/DK/NIDDK NIH HHS/United States
GR  - R01 HL093022/HL/NHLBI NIH HHS/United States
GR  - DK089507/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Cytokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-3)
SB  - IM
MH  - Animals
MH  - Cell Differentiation
MH  - Cytokines/genetics/*metabolism
MH  - Disease Models, Animal
MH  - Gene Expression Regulation
MH  - Genotype
MH  - Inflammation Mediators/*metabolism
MH  - Macrophages/immunology/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neutrophil Infiltration
MH  - Phenotype
MH  - Pneumonia/genetics/immunology/*metabolism
MH  - Time Factors
MH  - Tissue Inhibitor of Metalloproteinase-3/deficiency/genetics/*metabolism
PMC - PMC3931094
EDAT- 2013/06/08 06:00
MHDA- 2013/12/29 06:00
PMCR- 2014/11/01
CRDT- 2013/06/08 06:00
PHST- 2013/06/08 06:00 [entrez]
PHST- 2013/06/08 06:00 [pubmed]
PHST- 2013/12/29 06:00 [medline]
PHST- 2014/11/01 00:00 [pmc-release]
AID - 10.1165/rcmb.2012-0377OC [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 2013 Nov;49(5):768-77. doi: 10.1165/rcmb.2012-0377OC.